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首页> 外文学位 >Fully human antigen-specific polyclonal antibody responses induced in cloned human artificial chromosome transchromosomic cattle.
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Fully human antigen-specific polyclonal antibody responses induced in cloned human artificial chromosome transchromosomic cattle.

机译：在克隆的人类人工染色体转染色体牛中诱导的完全人类抗原特异性多克隆抗体反应。

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摘要

Methods for engineering mice to express polyclonal repertoires of human antibodies are well established and their use to produce human monoclonal antibodies of predefined specificity has been widely demonstrated (Ishida, et al., 2002; Lonberg, et al., 1994; Mendez, et al., 1997; Nicholson, et al., 1999). Although such engineered mice do expresses diverse repertoires of human antibodies and are immunophysiologically similar to humans; due to their small size, they are not suitable for the production of significant quantities of human polyclonal antibodies (hPAbs). Currently, hPAbs are in wide clinical use for prophylaxis and therapy in immunocompetent and immunodeficient patients [Keller, et al., 2000). Because these antibodies are obtained from human sources their supply is limited and their titers are often low because immunization protocols to raise pathogen-specific antibodies in donors are optimized for safety rather than for magnitude and duration of antibody response. Given these limitations, a technology for the production of antigen-specific hPAbs in large nonhuman hosts is novel and has significant biomedical and biodefense interest.; Considering the differences in the mechanisms and strategies used by bovines and humans to diversify their antibody repertoires (Butler, 1998; Flajnik, 2002; Reynaud, et al., 1991; Meyer, et al. , 1997), questions arise about the capacity of HACs to sponsor the generation of functional human Ig repertoires. This prompted the following critical questions to be addressed: Can a large and viable population of human Ig-producing cloned HAC-Tc cattle be produced? Does human Ig synthesis persist as the animals mature? Is any portion of the human Ig assembled as fully human antibodies free of bovine heavy or light chains? Do rearranged human heavy chain loci undergo class switching in bovine cells? Does the HAC construct encode a broad diversity of human immunoglobulins in cattle? Most importantly, does immunization induce any fully human, antigen-specific polyclonal antibodies in cloned, HAC-Tc cattle, and effect protective functions? Resolving these questions is necessary to determine if the immunological divergence of bovines and humans prevent the use of HAC-bovines as suitable bioreactors for production of human antibodies for therapy.; The availability of cloned HAC-Tc cattle that are imrnunologically mature has enabled the conduct of studies to address these questions, and the following results have been obtained. Biochemical and serological studies determine that fully human Ig isolated from HAC-Tc cattle is polyclonal and is comprised of both human mu and gamma isotypes, demonstrating that the HAC-borne human IgH locus undergoes class switching within bovine cells. (Abstract shortened by UMI.)
机译：工程小鼠表达人抗体多克隆库的方法已经很好地建立起来，并且已经广泛证明了其用于产生具有预定特异性的人单克隆抗体的用途（Ishida等，2002； Lonberg等，1994； Mendez等，等）。 （1997； Nicholson等，1999）。尽管这种工程小鼠确实表达了多种人类抗体，并且在免疫学上与人类相似。由于它们的体积小，它们不适合生产大量的人多克隆抗体（hPAb）。目前，hPAbs在具有免疫能力和免疫缺陷的患者中广泛用于预防和治疗[Keller，et al。，2000]。因为这些抗体是从人源获得的，所以它们的供应有限并且其效价通常很低，因为针对供体而不是针对抗体应答的大小和持续时间优化了在供体中产生病原体特异性抗体的免疫方案。考虑到这些限制，一种用于在大型非人类宿主中生产抗原特异性hPAb的技术是新颖的，并且具有重大的生物医学和生物防御意义。考虑到牛和人类用于多样化抗体库的机制和策略的差异（Butler，1998； Flajnik，2002； Reynaud等，1991； Meyer等，1997），人们对蛋白质的能力提出了疑问。 HAC赞助功能性人类Ig储备库的生成。这促使解决以下关键问题：是否可以生产大量可行的人类Ig克隆HAC-Tc牛？随着动物的成熟，人类的Ig合成会持续吗？是否将人Ig的任何部分组装成不含牛重链或轻链的完全人源抗体？重排的人重链基因座是否在牛细胞中经历类别转换？ HAC构建体是否编码牛中广泛的人类免疫球蛋白？最重要的是，免疫能否在克隆的HAC-Tc牛中诱导出任何完全人类的，抗原特异性的多克隆抗体，并影响保护功能？解决这些问题对于确定牛和人的免疫学差异是否阻止使用HAC牛作为生产治疗用人抗体的合适生物反应器是必要的。免疫学上成熟的克隆HAC-Tc牛的可获得性使得能够进行研究以解决这些问题，并且获得了以下结果。生化和血清学研究确定，从HAC-Tc牛分离出的完全人Ig是多克隆的，由人mu和γ同种型组成，这表明HAC携带的人IgH基因座在牛细胞内经历了类别转换。 （摘要由UMI缩短。）

著录项

  • 作者

    Choi, Yoon Jong.;

  • 作者单位

    University of Massachusetts Amherst.;

  • 授予单位 University of Massachusetts Amherst.;
  • 学科 Health Sciences Immunology.; Biology Molecular.; Biology Veterinary Science.; Agriculture Animal Culture and Nutrition.; Biology Genetics.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 159 p.
  • 总页数 159
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 预防医学、卫生学;分子遗传学;动物学;饲料;遗传学;
  • 关键词

  • 入库时间 2022-08-17 11:42:36

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